The combination of 5FU and leucovorin (LV) has resulted in significant increases in response rates and modest improvements in survival for patients with metastatic colorectal cancer. However, many patients are resistant to treatment at presentation and others acquire resistance during therapy. Resistance may be the result of provision of thymidylate via the alternate salvage pathway from intracellular or extracellular breakdown products of DNA. Persantine inhibits nucleoside transport at the cell membrane thereby blocking salvage of preformed nucleosides. Thus, extracellular nucleosides will be unable to enter the cell while lipid-soluble AZT can diffuse into the cell and compete with any thymidine generated by escape of TS inhibition by 5FU and LV or the intracellular salvage of nucleosides. The combination of these agents should lead to effective thymidine starvation and cell death. A phase I study using fixed doses of 5FU, LV and persantine with increasing doses of AZT (50 mg, 100 mg and 200 mg) has been completed. Dose-limiting toxicity was not observed and an AZT dose of 200 mg was chosen for the phase II study. Accrual to the phase II portion has been completed. Thirty-three patients were treated in the phase II portion of the study, with the major toxicity being hematologic. Four patients developed grade III and 21 patients developed grade IV neutropenia with six febrile neutropenic episodes. Six patients experienced grade III anemia and four grade III thrombocytopenia. Diarrhea or stomatitis of greater than or equal to grade III occurred in six and four patients, respectively. At the 200 mg AZT dose level, there were two partial responses in nine colorectal cancer patients (22%). Seven of these nine had received prior 5FU therapy. There were no objective responses in 14 patients with renal cell carcinoma or 14 melanoma patients.